Optical coherence tomography (OCT) is a powerful tool for assessing three-dimensional (3D) tissue architectural morphology in vivo and in real-time, with a resolution approaching that of standard histopathology. Optical coherence microscopy (OCM) combines OCT with confocal microscopy in order to achieve high transverse resolution and 3D visualization of cellular features. However, current OCT and OCM imaging technologies have not been able to leverage the advances in molecular-targeted contrast agents because there is no. known method to generate molecular contrast using OCT and OCM. Our hypothesis is that 3D, multi-scale OCT and OCM, in combination with molecular-targeted contrast agents, will improve the sensitivity and specificity of early cancer detection. The goal of this program is to develop the technology that will enable molecular contrast for 3D-0CT and OCM imaging, building upon preliminary studies. This program will vertically integrate technical development in OCT and OCM, and leverage recent advances in molecular-targeted contrast agents and nanotechnology. The successful completion of this program will: 1) transform the OCT field by enabling molecularly sensitive contrast and 3D structural imaging; 2) open the way for the highly sensitive and specific detection of cancer markers that can be readily combined with photothermal therapeutic techniques; and 3) serve as a launching point for additional OCT and OCM studies of other pathologies associated with abnormal protein expression levels, such as neurodegenerative and cardiovascular diseases. These advances will enable both the structure and pathological states of tissue to be imaged in 3D, in vivo, in real time, and with micron-level spatial resolutions at multiple scales.